A Highly Active and Selective Zirconium-Based Catalyst System for the Industrial Production of Poly(lactic acid)

The biodegradable, aliphatic polyester poly(lactic acid), PLA, is a leading bio-based alternative to petrochemical-derived plastic materials across a range of applications. Widely reported in the available literature as a benchmark for PLA production via the bulk ring-opening polymerization of lactides is the use of divalent tin catalysts, and particularly tin(II) bis(2-ethylhexanoate). We present an alternative zirconium-based system that combines an inexpensive Group IV metal with the robustness, high activity, control, and designed compatibility with existing facilities and processes, that are required for industrial use. We have carried out a comprehensive kinetic study and applied a combined experimental and theoretical approach to understanding the mechanism by which the polymerization of lactide proceeds in the presence of this system. In the laboratory-scale (20 g) polymerization of recrystallized racemic d,l-lactide (rac-lactide), we have measured catalyst turnover frequencies up to at least 56,000 h–1, and confirmed the reported protocols’ resistance toward undesirable epimerization, transesterification, and chain scission processes, deleterious to the properties of the polymer product. Further optimization and scale-up under industrial conditions have confirmed the relevance of the catalytic protocol to the commercial production of melt-polymerized PLA. We were able to undertake the efficient preparation of high-molecular-weight PLA on the 500–2000 g scale, via the selective and well-controlled polymerization of commercial polymer-grade l-lactide under challenging, industrially relevant conditions, and at metal concentrations as low as 8–12 ppm Zr by weight ([Zr] = 1.3 × 10–3 to 1.9 × 10–3 mol %). Under those conditions, a catalyst turnover number of at least 60,000 was attained, and the activity of the catalyst was comparable to that of tin(II) bis(2-ethylhexanoate).


Contents
. Plots of relative rate for reaction IR-25, the ROP of rac-LA in the presence of f1, with stepwise addition of aliquots of exogenous BnOH at four-minute intervals (indicated by vertical lines). Two plots have been constructed, using calibrated data corresponding to the LA and PLA signals, respectively. Labels refer to entries in Table S4 Figure S23. A visual representation of the chain growth anticipated to occur for the distribution of polymer chains corresponding to each initiation event in IR-25 (f1, followed by four aliquots of BnOH) in each four-minute interval, expressed as a percentage of the monomer feed, and the resulting theoretical molecular weight of each distribution, assuming all chains propagate at an equal rate at any given time .                         Aesar and used without further purification. All other chemicals were purchased from Sigma Aldrich.
Anhydrous benzyl alcohol, BnOH, was degassed under dynamic vacuum for 20 hours prior to use, and stored thereafter under dry argon. rac-LA and L-LA were recrystallized three times from toluene and then dried under dynamic vacuum for 16 hours, before storage under a dry argon atmosphere. The toluene was drawn directly from the solvent purification system and the recrystallizations carried out under ambient air. After each recrystallization the lactide was filtered over a sintered glass frit and washed sparingly with fresh SPS toluene. All other chemicals were used without further purification.
All NMR spectra were acquired using a 400 MHz ( 1 H), 101 MHz ( 13 C) Bruker Avance spectrometer, unless otherwise stated. CDCl3 was purchased from Sigma Aldrich and used as received for polymer analysis. For analysis of metal complexes, CDCl3 was dried over calcium hydride, distilled under vacuum, and stored over 4 Å molecular sieves under a dry argon atmosphere. Toluene-d8 was purchased from Sigma Aldrich and stored over 4 Å molecular sieves under a dry argon atmosphere.
Processing was carried out using Mestrelab Research MestReNova version 11.0.2-18153.
Crystallographic data was collected using a Supernova EOS detector diffractometer with Cu-Kα radiation (λ=14184 Å) at 150(2) K. Structures were solved using direct methods and refined on all F 2 data using the SHELXL-97 suite of programs. All hydrogen atoms were included in idealised positions and refined using the Riding model.
Polymer molecular weight data was acquired using an Agilent 1260 Gel permeation Chromatography (GPC) system equipped with triple detection (differential refractive index detector, viscometer and dual angle light scattering detector (90°/15°, only 90° data was used). A PLgel 5 μm MIXED-D 300 x 7.5 mm column was used, with a PLgel 5 μm MIXED Guard 50 x 7.5 mm guard column. The mobile phase was THF, at a flow rate of 1 ml min -1 . Columns and detectors were maintained at 35 °C. Data was processed using Agilent's GPC/SEC Software, Revision A.02.01. Unless otherwise stated, polymer samples were not purified prior to GPC analysis, and molecular weight values have been adjusted according to the final percentage conversion, as determined by 1 H NMR spectroscopy.
Thermogravimetric analysis was carried out using a Setaram Setsys Evolution TGA 16/18, equipped with a 170 μl alumina crucible. Samples of mass ~20 mg were heated to 1000 °C at a rate of 10 K min -1 , under a flow of dry argon. The furnace was purged with dry argon for 40 minutes prior to use, at a flow rate of 200 ml min -1 . Data was processed using the Calisto software package (version 1.41).

Synthesis of pro-ligand tris(2-hydroxy-3,5-dimethylbenzyl)amine, H3L Me
Pro-ligand H3L Me was synthesised according to the following adapted literature procedure. 1 To 818 mmol (100 g) 2,4-dimethylphenol was added 68.18 mmol (9.5 g) hexamethylenetetramine, 545 mmol (16.4 g) paraformaldehyde, and 2.72 mol (50 ml) of deionised water. The mixture was then refluxed with vigorous stirring for 120 hours in an oil bath at 150 °C, with two further 10 ml aliquots of 2,4-dimethylphenol added after 72 hours and 90 hours respectively. The reaction mixture was cooled and the resulting orange solid washed over a glass frit with 5 x 400 ml MeOH, to yield a white powder.
The powder was then dried under dynamic vacuum for 24 hours. 1 H and 13 C{ 1 H} NMR data in CDCl3 was in agreement with the literature. 1 Yield: 63 g, 55 %

Synthesis of pro-ligand tris(2-hydroxy-3-methyl-5-tert-butylbenzyl)amine, H3L Me/tBu
Pro-ligand H3L Me/tBu was synthesised according to the following adapted literature procedure. 2 To 85 mmol (9.6 g) 2-methyl-4-tert-butylphenol was added 4.9 mmol (0.68 g) hexamethylenetetramine, 38.9 mmol (1.17 g) paraformaldehyde, and 200 mmol (3.7 ml) of deionised water. The mixture was then refluxed with vigorous stirring for 120 hours in an oil bath at 120 °C, with two further 2.2 ml aliquots of 2-methyl-4-tert-butylphenol added after 72 hours and 90 hours respectively. The reaction mixture was cooled and the resulting yellow solid dissolved in methanol and precipitated by addition of water. The precipitate was isolated by gravity filtration (filter paper) and air dried, before recrystallization from hexane and drying under dynamic vacuum, yielding a yellow solid. 1

Synthesis of zirconium amine tris(2-hydroxy-3-methyl-5-tert-butyl) complex, Zr(HL Me/tBu )2, 2.
2 was prepared by an analogous procedure to 1. The air-and moisture-stable product was not recrystallized. 1 H and 13 C{ 1 H} NMR data for 2 in CDCl3 was in agreement with the literature. 2 The crystal structure of 2 is reported for the first time in the current work (see below). Yield: 1.5 g, 63 %

Solubility of catalyst 1 in toluene and o-xylene
For industrial relevance (economy, sustainability and safety), ambient-temperature storage and delivery of 1 in concentrated solution is desirable, ensuring compatibility with current infrastructure.
The solubility of 1 in high-boiling, industrially relevant, aprotic solvents was investigated. Using variable-temperature 1 H NMR spectroscopy, the solubility of 1 at various temperatures in toluene-d8 and o-xylene-d10 was assessed, by comparison with a 1,3,5-trimethoxybenzene standard.
In each case, a stock solution was prepared at 100 °C, of 33.4 mg of 1,3,5-trimethoxybenzene in 2 ml toluene-d8, or 11.7 mg of 1,3,5-trimethoxybenzene in 1.7 ml o-xylene-d10. To this, 1 was added stepwise until saturation was reached (23.8 mg was added to toluene, corresponding to a Zr concentration of ~1.3x10 -2 mol dm -3 , or 1.2 g L -1 , and 23.4 mg to o-xylene, corresponding to ~1.5x10 -2 mol dm -3 , or 1.4 g L -1 ). 0.6 ml of the relevant saturated solution was transferred to a J Young's NMR tube, and sealed under air. After cooling to -78 °C, the solution was left at ambient temperature for 20 hours, allowing precipitation of 1. 1 H NMR spectra were acquired at a range of ascending temperatures.
Prior to each acquisition, the temperature was increased to the required value and maintained for 5 minutes. The sample was then removed from the spectrometer, shaken vigorously and returned, whereupon the temperature was maintained for a further five minutes prior to data acquisition. 1 ml of toluene was found to dissolve at least 1 g of 1,3,5-trimethoxybenzene at ambient temperature (20 °C).
Accordingly, in the course of NMR solubility studies, the 1,3,5-trimethoxybenzene internal standard was assumed to be always fully dissolved. The concentration of 1 determined by comparison of integrated methyl 1 H resonances corresponding to both species.

Temperature, °C
The calculated solubility of 1 in toluene-d8 was corroborated by solvation of 1 in protio-toluene on a larger scale. At 70 °C, 15 ml of protio-toluene was required to solvate 120 mg of 1. This corresponded to a Zr concentration of ~0.8 g L -1 .
The discrepancy between the measured maximum solubility of 1 obtained using the two methods is likely due to experimental errors regarding the concentration of the 1,3,5-trimethoxybenzene standard during the NMR study, and evaporation of solvent during the larger-scale experiment.
However, the solubility in both cases was much too low to be industrially useful, and so further measurements were not made.

Rapid solubility screening of 1 in industrially relevant solvents
Other solvent systems were screened, in each case by dropwise addition of the relevant solvent to 100 mg of 1. Where solubility was lower than that of toluene and o-xylene (1.2 g L -1 ), the experiment was terminated. For industrial use, a Zr concentration of 3.5 g L -1 was targeted. Solubility was insufficient in all cases for industrial application (Table S1), with the exception of benzyl alcohol.
However, extensive heating was required to solubilise 1 in BnOH (120 mins at 180 °C), and it did not remain fully solvated on cooling to ambient temperature.
Solubility screening for each solvent was undertaken in a 30 ml vial, held in an aluminium block heated to the required temperature. The mass of solvent added to fully dissolve the solid material allowed determination of the concentration of 1.

Solubility of complex 2
It was anticipated that the presence of tert-butyl groups on the ligand framework of 2 would enhance solubility in hydrocarbon solvents, relative to 1. However, 2 was much less soluble in toluene than 1 (~0.33 g L -1 , 2.90x10 -1 g L -1 at 30 °C, decreasing with increased temperature).

Thermal stability of complexes 1 and 2
Thermogravimetric analysis showed that complex 2 was more thermally stable than complex 1. 1 decomposed in the temperature range 226-281 °C when heated from ambient temperature at 10 K min -1 , whereas 2 decomposed in the range 245-327 °C (inflection temperature = 247 °C and 287 °C, respectively; Figure S4), suggesting there would be an increased activation barrier for the ROP of LA in the presence of 2, relative to 1, via the proposed mechanism. Accordingly, the catalytic use of 2 was not investigated further. Notably, 1 did not undergo any decomposition event below 226 °C, suggesting that ligand dissociation does not spontaneously occur at the temperature used for the solvent-free ROP of lactides in the current work (≤180 °C), although this, alone, does not discount ligand dissociation occurring more readily in the presence of the monomer and/or co-initiator. The repeat unit of the oligomers, observed in the mass spectrum, was 72 g mol -1 , corresponding to a single lactic acid unit, rather than the dimeric LA monomer ( Figure S5). Thus, the presence of heavier oligomers was attributed to transesterification of e1 in the presence of a high concentration of complex 1 during formulation, rather than any significant non-living character with respect to polymerization catalyst 1. Oligomers with a 72 g mol -1 repeat unit comprising the co-initiating species in formulation f1 precludes use of MALDI-TOF-MS analysis of polymer products to identify or quantify any transesterification activity occurring during catalytic application of f1 to the ROP of lactides. The presence of diester e1 and heavier lactyl oligomers was supported by 1 H and 13 C{ 1 H} NMR analysis of f1 ( Figure S6). The concentration of Zr, introduced as catalyst 1, in f1 was experimentally determined to be 4.27x10 -2 mol dm -3 (3.90 g L -1 ) corresponding to 1 mol% with respect to the total number of benzyl residues, or alcohol groups present. This value was 2.847 x10 -2 mol dm -3 and 2.135 x10 -2 mol dm -3 for f2 and f3, respectively, used under industrial conditions to calculate ppm Zr catalyst loadings, see relevant section below. Catalyst degradation during formulation, the potential for error associated with the method used to determine [Zr]f1, and other measurement errors and variables arising from the formulation step make these values approximations. Nonetheless, they are used consistently throughout the current work, allowing valid investigation of the system for industrial application, and are supported by good agreement between theoretical and experimental polymer molecular weights. Although a solution of equivalent molar concentration of catalyst 1 can be prepared in neat BnOH, that system appeared to be less stable than f1, precipitating solid catalyst particles within one day on cooling to ambient temperature. This is incompatible with large-scale preparation and storage.
Scheme S1. Diester e1, the product of the ring-opening of one equivalent of lactide in the presence of a benzyl alcohol nucleophile, and heavier oligomers arising from transesterification of e1, comprising the solvent system of catalyst formulation f1  In addition to an increase in the concentration of 1 when compared to toluene, use of f1 does not introduce any exogenous solvent to the polymerization reaction mixture. The solvent system of f1, generated in-situ, serves as the external nucleophile (co-initiator) in the ROP of LA, thus forming part of the polymer chain. This enhances industrial relevance, and ensures ease of kinetic analysis.
Additionally, 1 remains solvated in f1 at ambient temperature for at least 18 months, increasing ease of handling and storage when compared to traditional solvent systems. Although the components of formulation f1 are air-and moisture-stable, the catalyst formulation was handled under a dry argon atmosphere at all times. This was to prevent contamination with protic impurities (moisture), which may negatively affect molecular weight control, prior to catalytic use.

In-situ ATR-FT-IR-monitored polymerization of rac-LA or L-LA 1.5.1 General procedure
A three-necked, jacketed glass reactor was loaded with 20 g of rac-or L-LA as required. A mechanical stirrer and Bruker IN350-T ATR-FT-IR insertion probe were respectively sealed into two of the vessel's necks. The third (central) neck of the reaction vessel was connected to a Schlenk line ( Figure S7).  Where indicated, the stereoselectivity of catalytic systems was calculated using both kinetic methods and polymer characterisation data. The former method used the relative rate constants, kobs(L- LA) and kobs(rac-LA), for the ROP of L-LA and rac-LA, respectively, using the method described by Nomura and co-workers. 7 Accordingly, polymer tacticity is given by: Pr=1-(0.5(kobs(L-LA)/kobs(rac-LA)), where Pr is the probability of heterotactic enchainment. 7 In the latter case, the tacticity of polymer samples was

Calibration of ATR-FT-IR reaction monitoring apparatus
The in-situ ATR-FT-IR reaction monitoring apparatus was calibrated using sample mixtures of PLA and rac-LA, of known molar composition, with respect to the number of lactyl groups (PLA:LA = 0:100, 20:80, 40:60, 60:40, 80:20, and 100:0, respectively). Following acquisition at 174°C of ATR-FT-IR spectra corresponding to each sample, a calibration curve was constructed, describing the relationship between the integrated area of the LA signal and the concentration of LA ( Figure S11). However, any temperature dependence of the ATR-FT-IR LA signal area was shown to be negligible ( Figure S12, Figure S13). Thus, for simplicity, ATR-FT-IR data obtained at all temperatures (determination of ΔG ‡ ) was processed using the calibration curve corresponding to a reaction temperature of 174 °C. Additionally, the calibration data obtained using rac-LA was assumed to be valid for manipulation of kinetic data corresponding to the polymerization of L-LA.    For reactions IR-14, IR-15, IR-6, IR-16, IR-7, IR-17, (Table S3) the concentration of the monomer was plotted against time ( Figure S17). The reaction time required to reach, for example, 50 % conversion, was much higher for reaction IR-14, than for any other reaction. It is therefore plausible that catalyst deactivation occurred to a much greater extent in that system, than in any of the other reactions, leading to deviation from a first order rate dependency with respect to the catalyst concentration.  Table S3.

Plots of lactide concentration versus time for comparison of solid 1 and formulation f1
Comparison of the reaction kinetics afforded by solid catalyst 1 (with exogenous BnOH) and formulation f1, respectively, were compared at two catalyst loadings. Whereas the reaction profiles corresponding to use of f1 (IR-6, IR-7)described smooth curves, characteristic of pseudo-first order reaction kinetics, those produced using the solid catalyst were erratic and unpredictable. The latter reactions were, for this reason, repeated, with the unpredictable nature of the kinetics thus being confirmed.  Table 3 of the main paper.

Initial rate analysis
The propagation rate constant, kp, for the solvent-free ROP of rac-LA at 174 ˚C in the presence of f1, was obtained via initial rate analysis, informed by VTNA (above, Table S3, Figure S18) as described in the main paper. Semi-logarithmic plots were used to determine the observed rate constant kp at each of several catalyst loadings ( Figure S19), and these values plotted against the catalyst concentration ( Figure 6 in main paper) to provide kp. Figure S19. Semi-logarithmic initial-rate plots for the ROP of rac-LA in the presence of f1. Labels refer to entry numbers in Table S3.

Addition of exogenous alcohol during polymerization
The effect of varying the molar [Zr]:[ROH] ratio on the rate of ROP was assessed by addition of exogenous BnOH to the ROP of rac-LA in the presence of f1. Figure S20. Semi-logarithmic plots corresponding to reactions carried out to investigate the effect of exogenous BnOH on the ROP of rac-LA in the presence of f1. Vertical lines denote addition of BnOH. Labels refer to entries in Table S4.  Table S4).
The initial rate was in excellent agreement with that of IR-6, but a significant rate increase was observed after the first introduction of 0.80 mol% BnOH, with subsequent additions eliciting a much smaller effect, as would be expected at higher conversion. In a plot of [LA] versus time, a brief period of very fast conversion was visible immediately after each addition of BnOH, suggesting rapid consumption of the primary alcohol ( Figure S21. Similarly, when the relative rate of LA consumption, -d[LA]/dt, was plotted against time, large maxima were present both after initial injection of f1, and after each subsequent addition of BnOH ( Figure S22). This is attributed both to the rapid initiation, relative to propagation, characteristic of an immortal regime, and to a proposed inverse relationship between chain length and propagation rate.  Table S4.
Each maximum in the plot of relative rate against time was immediately followed by a corresponding minimum, suggesting that injection of the exogenous alcohol at a location directly proximate to the ATR-FT-IR insertion probe, created a particularly large localised rate increase, which was followed by homogenisation of the mixture under mechanical stirring.  ). In that case the rate was higher than when f1 alone was used (IR-6), but did not significantly exceed that of IR-25 after addition of only 0.8 mol% of exogenous BnOH. The increased rate was observed from the beginning of the reaction, and a first order rate dependence on the loading of f1 used has been observed throughout the current work, allowing viscosity to be eliminated as the origin of the rate increase at higher alcohol concentrations. Similarly, the influence of differences in the respective steric and electronic properties of BnOH and polymer chains were ruled out on the basis that the rate discrepancy was clear throughout the reaction, from initiation to attainment of at least 70% conversion.
It is most plausible that the rate difference between IR-6 and the reactions to which exogenous The molecular weight of the main polymer product distribution of reaction IR-25, Mn GPC = 5650 g mol -1 , was in agreement with the theoretical value for the heaviest product fraction, Mn Theo = 5500 g mol -1 , calculated on the basis of five separate initiation events occurring, and the ROP adhering to ideal immortal ROP kinetics with negligible transesterification or chain scission activity. The percentage of the total monomer feed accounted for by each of the resulting polymer distributions was calculated from the percentage conversions reached at the time that each aliquot of BnOH was introduced ( Figure S23).
The lighter distributions were not detected via GPC indicating that when the PLA was purified by precipitation from methanol those product fractions remained in the solution phase, although a tail toward low molecular weight indicated that some low-weight chains were present.

Kinetic isotope study 2.3.1 General procedure
Analysis of heteroselectivity suggests that, as expected, the active species is the same for the ROP of LA in the presence of 1 and f1, respectively. Accordingly, the kinetic isotope study was undertaken using deutero-and protio-ethanol, which is readily obtained from commercial suppliers, whereas deuterated benzyl alcohol, BnOD is not. As preparation of a formulation such as f1 is not possible with ethanol, the catalyst, 1, and 100 equivalents (to ensure consistency with f1) of the co- toluene relative to in the oligomer-based solvent phase of f1. However, it has been shown in the ex-situ kinetic study of the ROP of rac-LA catalyzed by f1, that on a 1 g scale, in a sealed J Young's ampoule, kinetics representative of the rate law can be observed in the presence of 3.1x10 -3 mol% 1. Therefore, we used 3.1x10 -3 mol% 1 for the kinetic isotope study, thus ensuring that the volume of toluene added to the polymerization (65 μl per 1 g of LA) was sufficiently small for the reaction to still be considered to occur under a solvent-free regime. The kinetic isotope study was carried out at a lower temperature, 150 °C, in order to reduce the relative reaction rates, and aid identification of any kinetic isotope effect.
The more laborious parallel reactions method was used for this study, with all conversion values reactions, a semi-logarithmic initial rate plot was constructed for determination of kobs ( Figure S26). The crude products were analysed by GPC, with data appropriately adjusted to account for conversion.
The rate constant kobs for the protio system at 150 °C (1.66x10 -2 min -1 ) was very similar to observed that for the ex-situ kinetic study with 3.1x10 -3 mol% 1 dosed as f1, carried out at 174 °C (1.58x10 -2 min -1 ). The occurrence of similar rates, despite a large temperature difference, can be attributed to catalyst deactivation due to the prolonged heating in the presence of a high alcohol concentration, required during preparation of f1 (the use of a different alcohol is not significant after the non-rate-determining initiation step). However, as previously discussed, delivery of 1 as a saturated solution in toluene is not a viable method for producing PLA on an industrially relevant timescale without introducing unacceptably large volumes of toluene to the polymerization vessel.   Table S6.

Experimental determination of ΔG ‡ for the rate-determining step of propagation in the ROP of rac-LA initiated by f1
Determination of ΔG ‡ for the ROP of rac-LA at 174 ˚C was carried out via construction of an Eyring plot, using rate constants, kobs, obtained through initial rate analysis of four solvent-free polymerizations, undertaken at temperatures between 144 ˚C and 174 ˚C (Table S7, Figure S27, Figure   S28). The value obtained, ΔG ‡ = +32.5 kcal mol -1 , was satisfactorily consistent with the calculated value for the initiation step of the proposed mechanism (ΔG ‡ = +39.6 kcal mol -1 ). The experimental value of ΔG ‡ confirms the validity of the other kinetic studies undertaken in the current work, whilst the computational studies have enabled elucidation of an accessible mechanistic pathway consistent with all experimental observations, and allowed the other apparent possibilities to be eliminated.
Due to the greater entropy associated with the presence of a growing polymer chain during propagation, than with the single BnOH molecule present during the modelled initiation event, it is assumed that the ΔG ‡ value calculated for initiation will exceed that of the more readily measured propagation event (which will exhibit some variation for each sequential chain growth event), in closer agreement with the experimental value. Due to the large size of the catalytic system it was not feasible to model propagation as well as initiation, especially given the expected mechanistic similarity of the two processes. Whilst the ROP of L-LA was considered in-silico, the experimental value was obtained using rac-LA, to ensure consistency with the wider kinetic study. Nonetheless, given the optical inactivity of 1, and the stoichiometric nature of the modelled system (only a single monomer molecule was present in the system modelled), it is not anticipated that the calculated value of ΔG ‡ of initiation would differ significantly for D-LA. Moreover, in propagation, ΔG ‡ for heterotactic enchainment will be slightly lower in the presence of 1 than ΔG ‡ for isotactic enchainment (corresponding to heteroselectivity described by Pr = 0.67 for the ROP of rac-LA in the presence of 1, and isotactic enchainment being necessary in the presence of an enantiopure L-LA feed). Accordingly, an experimentally obtained value of ΔG ‡ for propagation in the ROP of L-LA would be anticipated to exhibit closer agreement with the calculated value. ) + , + , }. c Determined via GPC analysis in THF using Triple Detection. d Rate constants determined by initial rate analysis via in-situ ATR-FT-IR spectroscopic reaction monitoring. Figure S27. Initial rate plots for the ROP of rac-LA in the presence of f1 constructed using data gathered at temperatures between 144 ˚C and 174 ˚C. Labels refer to entry numbers in Table S7.  (Table S14, Figures S40, S41). In consistency with other formulation-initiated polymerizations reported in the current work, and reflecting the many variables associated with catalyst formulation prior to use, including co-initiation by an ill-defined oligomeric mixture, use of several different catalyst formulations, and of an unpurified LA feed, theoretical molecular weights, Mn Theo have been reported to the nearest 500 g mol -1 only.
In none of the experiments described was any indication of depolymerization activity by 1 observed under the ROP conditions. PLA from reaction IE-3 underwent several processing steps, including multiple thermal processes, to yield crystalline resin pellets. The resulting pellets were then stored under air for 12 months, after which GPC analysis revealed only a modest reduction in Mn relative to that of the crude product, analysed prior to processing, from 37 700 g mol -1 to 29 500 g mol -1 . ĐM increased slightly, from 1.30 to 1.43. Such stability toward depolymerization and chain scission (hydrolysis) during processing and storage, regardless of the continued presence of Zr, appears sufficient for many short-and medium-term applications, without the need for stabilization. Table S8. Polymerization data for the ROP of L-LA in the presence of catalyst formulations f1, f2, and f3, under industrial conditions (reproduced from main paper) Figure S29. Semi-logarithmic plots for the ROP of L-LA catalyzed by formulations f1, f2, f3, and Sn(Oct)2 under industrially relevant conditions. Labels refer to entry numbers in Table S8.
Additional formulation f1 was dosed into polymerization IE-1 after 2 hours reaction time had elapsed, and the polymerization continued for 1.5 hours thereafter. Accordingly, the GPC data obtained from the 120 minute sample exhibits a bimodal polymer molecular weight distribution, not seen in that    Conversion, %  Conversion, %  Conversion, %  Conversion, %  Conversion, %   Table S14.      Table S15.

1 H NMR spectra of PLLA samples
Samples of PLLA were analysed via 1 H NMR spectroscopy. In the cases of reactions L-1 and L-2, homonuclear decoupling refers to broadband decoupling of the methine signal of the polymer backbone, δH = 5.16 ppm from the adjacent methyl group. In the current work, this treatment produced a large singlet, corresponding to the iii tetrad ( Figure S53, Figure S54). No significant signals corresponding to other tetrads were observed, consistent with highly isotactic PLA, and negligible epimerization activity. 4

Differential Scanning Calorimetry of the crystallised product of reaction IE-3
Thermal analysis (DSC) of the crystalline pellets produced from the product of reaction IE-3 revealed the presence of a melting event with maximum negative heat flow occurring at 173.25˚C, consistent with literature values for isotactic PLLA of comparable molecular weight, and confirming the absence of epimerization. 10 Figure S56. DSC data corresponding to the crystalline PLLA product of reaction IE-3.

General Procedure
Complex 2 ( Figure S57), prepared in the current work to assess the effect of tert-butyl functionalisation of the ligand framework on the solubility of the catalyst in non-polar media, has previously been reported by Tasker and co-workers. 2 Although 2 was not applied to the ROP of lactides, a solid state structure for this species was obtained for the first time in the current work, and is therefore presented here ( Figure S58).
Consistent with the greater thermal stability of 2 than 1 (see above), the Zr-O bond lengths of 2 were found to be shorter than those of 1 (2.0576 (14)

Computational analyses
We reproduce here the section on computational analysis presented in the main text, with addition of schemes corresponding to all evaluated scenarios, and other useful discussion.
Computational methods, specifically density functional theory (DFT), were applied to the mechanistic analysis of the ROP of LA in the presence of 1 and BnOH, due to the catalyst's apparent structural incompatibility with standard coordination-insertion or activated monomer mechanisms, and the difficulty of experimentally delineating a mechanistic pathway under the conditions of use.
Due to the size of the catalytic system (involving up to 159 atoms in the initiation step), a layered basis set protocol (6-311+g(d) for N and O atoms, 6-311++g(d,p) for H from NH and OH groups, 6-31g(d) for all C and H atoms, except CH3 groups on aromatic rings (STO-3G)), involving the Stuttgart/Dresden effective core potential (SDD ECP) and associated basis set for the zirconium center, was used.
Calculations were initially carried out using PBE0 functional augmented with Grimme's empirical dispersion correction D3. 11 to PBE0 functional is a hybrid functional, which mixes the Perdew-Burke-Ernzerhof (PBE) exchange energy and Hartree-Fock exchange energy (25%), along with the full PBE correlation energy. 12 It had been repeatedly found to generate good geometries for transition metal complexes, and performed well for Zr-mediated reaction barriers in benchmark studies (with Mean Unsigned Deviations (MUD) less than 2 kcal/mol). 13 To best approximate solvation in molten LA and PLA, the solvent phase was modelled as ethyl acetate, using a self-consistent reactioncavity continuum solvation model (cpcm). 14 Further computational work therefore considered two mechanistic scenarios in which both ligands remained in-situ at the metal center: 1. Formation of a benzyl alkoxide complex, IV, by protonation of one phenolate 'arm', followed by a coordination-insertion mechanism (Pathway A, Scheme S3).
2. An activated monomer mechanism wherein the Lewis acidic metal center of 1 activates the monomer carbonyl moiety. proton to the phenolate arm. This was highly unfavorable. For formation of the L-LA complex, ΔG = +45.1 kcal mol -1 , and the barrier to nucleophilic attack at the monomer by the alkoxide was determined to be ΔG ‡ = +58.7 kcal mol -1 . These values are considered insurmountable under the current conditions.
Finally, dissociation of a second phenolate arm from the first ligand (Pathway C, Scheme S3), via transfer of the respective NH + proton, and coordination of LA at the vacant site, was considered.
It was also necessary to consider a classical Lewis-acid catalyzed activated monomer mechanism, without dissociation of a phenolate arm. As expected, DFT modelling showed that due to the coordinative saturation and extensive steric congestion about the Zr center of 1, interaction with the monomer to form binary complex VIII, (Scheme S4) was entirely obstructed. The simultaneous activation of alcohol and monomer species facilitates nucleophilic attack at the monomer carbonyl group, with a transition state energy of ΔG ‡ = +33.6 kcal mol -1 . This is considered accessible under the polymerization conditions, and is lower than for all alternative pathways. This activity corresponds to a ligand assisted activated monomer mechanism, reminiscent of that reported by Carpentier and co-workers, which has not been previously reported for an industrially relevant system. 16 When the system was modelled without the metal-LA interaction (IX*, Scheme S4), nucleophilic attack by the activated alcohol was very inaccessible, with a transition state energy of ΔG ‡ = +51.5 kcal mol -1 . Dissociation of the ligand arm from the metal center, and hydrogen bonding to the alcohol, without occupation of the vacant metal coordination site, is also highly unfavorable; ΔG = +43.9 kcal mol -1 .
Following nucleophilic attack on the activated LA molecule (IX, Scheme S4), the resulting quaternary species, X (Scheme S5), (ΔG = +22.3 kcal mol -1 ) can undergo ring opening to yield a free alcohol chain hydrogen bonded to the dissociated ligand arm to give structure XI, via transition state TSX-XI; ΔG ‡ = +39.6 kcal mol -1 . This was calculated to be much more favorable than ring-opening with retention of the Zr-O bond to yield a metal alkoxide chain, to give structure XII through rotation of the monomer to give intermediate X*, then via transition state TSX-XII; ΔG ‡ = +67.6 kcal mol -1 . Intermediate XI is additionally stabilized by coordination of the benzyl lactate carbonyl moiety to the Zr center, reminiscent of intermediate IX.
Finally, coordination of the ligand arm back to the metal center is favorable, yielding a binary complex of 1 and the growing chain (alcohol), XIII, (ΔG = +6.7 kcal mol -1 ), analogous to intermediate III. This is anticipated to be the resting state of the catalyst during propagation, and is clearly relevant to the subsequent addition of further equivalents of the monomer to the growing chain. Decomposition of the binary complex to yield the free alcohol chain and catalyst 1 has been calculated to be thermodynamically neutral; ΔG = 0.2 kcal mol -1 .

Scheme S5. Energetically inaccessible ligand-dissociation and zirconium benzyl alkoxide formation
Such slight endergonicity in the modelling of LA ROP has been previously observed by Gibson and Rzepa, 17,18 among others. 19 As only the initiation step was modelled, the limiting free energy of the ROP process has not necessarily been accurately represented. Indeed, with an increased number of monomer units, the entropy of the system is anticipated to increase and the free enthalpy of polymerization is therefore expected to become more favorable as polymerization progresses, in agreement with the experimental value of ΔG ‡ . Accordingly the Gibbs Free Energy profile for the initiation step, using the PBE0-D3 protocol is shown in Figure S59, and propagation is expected to be mechanistically analogous, commensurate with 1 being a catalyst, rather than a pre-catalyst. Because the mechanistic pathway has been delineated based on comparison of calculated activation barriers, all transition states were re-optimized and computed using different functionals (ωB97XD and M06-D3) for comparison (Table S16, Figure S60). Those calculations further support the proposed LAAM ROP mechanism. Figure S59. Energetic profile for the favored mechanism of ROP calculated using the PBE0-D3 protocol   (Table S17).
The lowest-energy transition states and the favorability of the LAAM mechanism were retained at that temperature. The limiting activation barrier for the LAAM pathway at 25 °C was ΔG = +24.5 kcal mol -1 , consistent with literature values for other ROP processes at the same temperature.